Comments from Karen White: "The met ID study for 3 compounds in human and rat hepatocytes has now been completed and the results are summarised in the attached report. Regarding the aldehyde oxidase question, one of the compounds did form an oxygenated metabolite which may or may not be mediated by AO (can also be mediated by CYP enzymes) but we couldn’t definitively tell the site of oxygenation from the available data or the enzyme responsible."

Initial analysis from Paul Willis: "Metabolite ID has shown that the 3 compounds all appear to undergo oxidation on the triazolpyrazine ring. This could be CYP or aldehyde oxidase mediated, further experiments are planned next year to determine which process is operating. At this stage the project should evaluate the existing data to see if either changes to the bulk properties (Log P etc.) or remote changes can increase metabolic stability. This may indicate a strategy for designing new more stable analogues. Blocking groups could also be introduced into the labile positions of the triazolopyrazine ring to further improve metabolic strategy. Given the likely synthetic challenges of such an approach, the project is recommended to wait until the full results of the metabolism experiments are available to guide such a strategy."